There is evidence that metabolic responses of parenchymal cells in different areas of the microcirculatory lobular unit of the liver are not uniform. A functional differentiation exists, due to a heterogeneous distribution of enzymes and gradients of substrates across the liver lobule. The implications of this heterogeneity for the hormonal regulation of liver metabolism form the subject of this study. Two basic aspects of the interaction of hormones with the heterogeneous organization of liver metabolism will be investigated. Firstly, a heterogeneous metabolic response across the liver lobule may reflect a differential distribution of hormone receptors on the cells. A separation of functionally diverse cells by their capacity to recognize specific hormones in affinity chromatography is a main objective of this project. This will allow a study of differences in the distribution of various hormone receptors and the mutual interaction of hormonal effects. Of particular interest is the possibility that changes in the distribution of specific hormone receptors across the lobular unit occur in response to different diets or in diabetes. Secondly, the hormonal state may affect the differential response of liver cells to substrate gradients. This study will focus on the metabolic effects of ammonia and its interaction with amino acid metabolism. A gradient of ammonia, as it occurs in the liver in vivo, would strongly influence the metabolic fate of amino acids. In diabetes, where liver metabolism is geared to gluconeogenesis from amino acids, the response to varying concentrations of ammonia may be modified. Important parameters to be studied are the redox states of NAD(P) in mitochondria and cytosol, which are changed, both after short-term treatment with glucagon or other hormones, and during long-term changes in the hormonal state, as in diabetes. This may be related to modifications in mitochondrial transport characteristics and reflects the altered metabolic orientation of the liver. A careful study of these aspects may contribute to an understanding of the intra- and intercellular organization of hormonal regulation in liver and of the metabolic defects observed in diabetes.